Potent in vitro and in vivo antitoxoplasma activity of the lipid-soluble antifolate trimetrexate.
AUTOR(ES)
Allegra, C J
RESUMO
Trimetrexate, a highly lipid-soluble quinazoline antifolate now undergoing trials as an anticancer agent, was found to be a potent inhibitor of the dihydrofolate reductase (DHFR) isolated from Toxoplasma gondii. The concentration required for 50% inhibition of protozoal DHFR was 1.4 nM. As an inhibitor of this enzyme, trimetrexate was almost 600-fold (amount of antifolate required to inhibit catalytic reaction by 50%) and 750-fold (inhibition constant) more potent than pyrimethamine, the DHFR inhibitor currently used to treat toxoplasma infection. When the protozoan was incubated with 1 microM trimetrexate, the drug rapidly reached high intracellular concentrations. Since toxoplasma organisms lack a transmembrane transport system for physiologic folates, host toxicity can be prevented by co-administration of the reduced folate, leucovorin, without reversing the antiprotozoal effect. The effectiveness of trimetrexate against toxoplasma was demonstrated both in vitro and vivo. Proliferation of toxoplasma in murine macrophages in vitro was completely inhibited by exposure of these cells to 10(-7) M trimetrexate for 18 h. When used alone, trimetrexate was able to extend the survival of T. gondii-infected mice.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=424107Documentos Relacionados
- Potent antipneumocystis and antitoxoplasma activities of piritrexim, a lipid-soluble antifolate.
- Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations.
- Activity of lipid-soluble inhibitors of dihydrofolate reductase against Pneumocystis carinii in culture and in a rat model of infection.
- Lipid-soluble components in cigarette smoke induce mitochondrial production of reactive oxygen species in lung epithelial cells
- DIURNAL VARIATION IN THE URINARY EXCRETION OF NEUTRAL LIPID-SOLUBLE REDUCING STEROIDS IN CONGESTIVE CARDIAC FAILURE AND CIRRHOSIS OF THE LIVER WITH ASCITES 12